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DR. ANASTASIOS KOLLIAS (Orcid ID : 0000-0002-2098-1665)

Article type : Short Reports

Heterogeneity in reporting venous thromboembolic phenotypes in COVID-19:

Methodological issues and clinical implications

Anastasios Kollias*; Konstantinos G Kyriakoulis*; George S Stergiou; Konstantinos Syrigos

National and Kapodistrian University of Athens, School of Medicine, Third Department of

Medicine, Sotiria Hospital, Athens, Greece

*these authors contributed equally

Word count: 620 References: 15 Tables: 1 Figures: 1

Correspondence: Anastasios Kollias, MD, PhD

National and Kapodistrian University of Athens,

School of Medicine, Third Department of Medicine,

Sotiria Hospital, 152 Mesogion Avenue,

Athens 11527, Greece.

Tel: +30 2107763117

Email: taskollias@gmail.com

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Abstract

COVID-19 is associated with increased risk of venous thromboembolic events (VTE). However,

there is significant heterogeneity in the thromboembolic phenotypes of COVID-19 patients (deep

vein thrombosis, pulmonary embolism/thrombosis). The latter might be partly attributed to the

variation in VTE risk factors in COVID-19 patients including: (i) patients’ characteristics; (ii)

hospitalization conditions and interventions; (iii) SARS-Cov-2 specific factors (coagulopathy,

endothelial injury/microthrombosis). Furthermore, there is methodological heterogeneity in

relation to the assessment of VTE (indications for screening, diagnostic methodology, etc).

Physicians should be aware of the increased VTE risk, strongly consider VTE screening, and use

thromboprophylaxis in all hospitalized patients.

Keywords: SARS-CoV-2; pulmonary embolism; deep vein thrombosis; prevalence

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Accumulating evidence suggests that severe coronavirus disease 2019 (COVID-19) is associated

with an increased venous thromboembolic risk.1,2 It appears that SARS-CoV-2 in severe cases

induces an excessive immune response associated with cytokine storm leading in turn to

coagulation disorders.1.2 The latter can be observed at both local level with lung endothelial injury

and microthothrombosis, as well as at systematic level with disseminated intravascular

coagulopathy.1,2

In light of the emerging evidence on the thromboembolic risk in COVID-19, recent publications

highlight 2 important issues: First the high rate of venous thromboembolism events (VTE) in

COVID-19 patients, and second the variety of the observed thromboembolic phenotypes. Indeed,

11 recent studies reported both the prevalence of deep vein thrombosis (DVT) and pulmonary

embolism (PE) in COVID-19 patients with prevalence numbers ranging from 0% to as high as

54% (Table 1).3-13 Importantly, there was no consistent relationship between the reported

prevalence of DVT and PE. It should be mentioned that most studies have included mainly

patients in intensive care unit (ICU) who presumably had severe COVID-19 (Table 1). One

study reported that the prevalence of VTE was significantly higher in ICU versus general

ward patients (47% and 3% respectively).6

These data indicate that there is heterogeneity in the reported VTE risk – although recognized by

all as increased - as well as in the thromboembolic phenotypes of COVID-19 patients (isolated

DVT, isolated pulmonary embolism/thrombosis, concurrent DVT and pulmonary

embolism/thrombosis). It might be suggested that variation in several VTE risk factors in COVID-

19 patients accounts for this observed heterogeneity which are presented in Figure 1 and include:

(i) characteristics of the patients including well-established risk factors for VTE; (ii)

hospitalization conditions and interventions; (iii) SARS-Cov-2 specific factors.

Further to the above, an additional important issue is the heterogeneity in the methodology used

across studies to identify VTE in COVID-19 patients. Indeed, factors that might play a role

include: (i) indications for VTE screening; i.e. consecutive patients or selected ones upon clinical

(respiratory or hemodynamic deterioration) or biochemical (increase in d-dimer values) suspicion,

and (ii) the diagnostic methodology applied i.e. ultrasonography or computed tomography Acc

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pulmonary angiography or both, which is largely dependent on the available human and

equipment resources.

Interestingly, even in studies which reported screening for DVT with leg compression

ultrasonography in all their patients, there has been significant heterogeneity. Specifically, Ren et

al reported that among 48 critically ill COVID-19 patients hospitalized in the ICU, 41 (85%)

presented with lower extremity DVT, mainly in the pattern of isolated distal DVT.14 On the

contrary, in another study in 64 COVID-19 patients hospitalized in general ward, none was found

with DVT.15 The two studies included patients with similar age (median 70 years) and gender

distribution, yet the former study included patients admitted in ICU with a more severe disease

and 7-fold higher d-dimer levels.14,15 It should be mentioned that thromboprophylaxis was

administered in both studies.14,15

The role of the d-dimer assessment and of optimal thromboprophylaxis in COVID-19

patients is of paramount importance. Some studies have shown that increased d-dimer

predict the development of VTE.3,6,9 Thus, patients with increased d-dimer values on

admission or increasing d-dimer values during their hospitalization should be candidates for

VTE screening. Moreover, several societies now recommend the use of thromboprophylaxis

in all hospitalized patients.1 Although prophylactic dosing is generally recommended, some

experts consider the use of intermediate dosing but relevant studies are lacking.

In summary, and in terms of clinical practice, physicians dealing with COVID-19 patients should

be aware that: (i) The risk of venous thromboembolism is high, yet with variable incidence of

phenotypes (DVT and PE); (ii) All hospitalized patients require thromboprophylaxis, yet the

optimal dosing is uncertain; (iii) VTE screening should be strongly considered and influenced by

clinical and biochemical characteristics (d-dimer).

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Authors’ contributions

AK and KGK performed the research and drafted the manuscript

GSG, KS provided critical review and supervision

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Table 1. Main characteristics and findings of studies.

Study Setting NAge, ys

±SD (range)Males (%)

Prevalence of

DM/CVD/PD (%)

Median (range)

SOFA/PaO2/FiO2

Antithrombotic

treatment dosing

Prevalence of

DVT/PE (%)

d-dimer (μg/ml; median

values) and predictive

value (ratio and 95% CI)

Stoneham et al.3 General ward 274 VTE 67±12 VTE 67 VTE 38/29/38 NR NR 2/6

VTE vs nonVTE: 4.1 vs 1.2

Adjusted OR for VTE: 1.4

(1.2,1.8)

Wright et al.4 ICU 44 54 (19-86) 64 41/NR/148 (7-10)/163

(127-235)Prophylactic 25/0 1.8 (0.9-4.1)

Thomas et al.5 ICU 63 59±13 69 NR NR Prophylactic 2/8 0.4 (0.1-3.6)

Middeldorp et al.6General ward 62%;

ICU 38%198 61±14 66 NR NR

Mainly

prophylactic13/7

VTE vs nonVTE: 2.6 vs 1.0

Subhazard ratio for VTE:

1.4 (1.1,1.9)

Helms et al.7 ICU 150 63 (53-71) 81 20/48/148 (5-10)/125 (97-

170)

Mainly

prophylactic2/17 2.3 (1.2-20.0)

Lodigiani et al.8General ward 84%;

ICU 16% 388 66 (55-85) 68 23/33/9 NR Mixed doses 2/3

Rapid increase in d-dimer in

non-survivors

Poissy et al.9 ICU 107 PE 57 (29-80) PE 59 NRPE

4 (0-4)/NRProphylactic 5/21

Subhazard ratio for PE: 1.8

(1.0,3.2)

Tavazzi et al.10 ICU 54 VTE 68±7 NR NR NR Prophylactic 15/6 NR

Llitjos et al.11 ICU 26 68 (52-75) 77 NR3 (2-5)/87 (74-

116)

Mainly

therapeutic54/23 1.8 (1.1-2.9)

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Beun et al.12 ICU 75 NR NR NR NR NR 4/27 NR

Klok et al.13 ICU 184 64±12 76 NR NRMainly

prophylactic2/35 NR

CVD, cardiovascular disease; DM, diabetes mellitus; DVT, deep vein thrombosis; ICU, intensive care unit; NR, not reported; OR, odds ratio; PD, pulmonary disease; PE, pulmonary embolism; SOFA, Sequential Organ Failure

Assessment; VTE, venous thromboembolism

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Figure 1. Factors increasing the venous thromboembolism risk in COVID-19.

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